Role of TGF-β1/Smad3-mediated fibrosis in drug resistance mechanism of prolactinoma
Role of TGF-β1/Smad3-mediated fibrosis in drug resistance mechanism of prolactinoma
复制标题
TGF-β1/Smad3 介导的纤维化在催乳素瘤耐药机制中的作用
DOI：
10.1016/j.brainres.2018.07.024
复制
发表时间：
2018-11-01
期刊：
影响因子：
2.9
通讯作者：
Wang, Haijun
中科院分区：
文献类型：
--
作者：
Hu, Bin;Mao, Zhigang;Wang, Haijun
泌乳素瘤是最常见的功能性垂体腺瘤。虽然多巴胺激动剂是治疗性治疗的主要方法，但对这些药物的耐药率每年都在持续增加。在以前的长期临床研究中，我们发现部分耐药的泌乳素腺瘤比敏感的腺瘤表现出更多的纤维化，这表明纤维化在其耐药性中的作用。此外，具有广泛纤维化的耐药腺瘤主要表达I型和III型胶原。由于TGF-β 1是组织纤维化（包括垂体）发生和发展的关键因素，因此在本研究中，我们旨在确定TGF-β 1是否介导泌乳素瘤的纤维化，以及纤维化是否与泌乳素瘤的耐药性有关。使用免疫化学和蛋白质印迹法，我们发现，TGF-β 1/Smad 3信号通路相关的蛋白质在高纤维化程度的催乳素瘤耐药标本中升高，与敏感样本中的水平相比，这表明该通路可能在催乳素瘤纤维化中发挥作用。在体外，TGF-β 1刺激促进正常HS 27成纤维细胞中的胶原蛋白表达。此外，大鼠泌乳素瘤MMQ细胞对溴隐亭的敏感性下降时，他们与用TGF-β 1处理的HS 27细胞共培养。TGF-β 1 Smad 3信号特异性抑制剂SB 431542抵消了这些作用，表明TGF-β 1/Smad 3介导的纤维化参与了泌乳素瘤的耐药机制。这些结果表明，SB 431542可能作为一个有前途的新的治疗方法，用于预防纤维化和进一步改善泌乳素瘤的耐药性。(C)2018爱思唯尔B. V.保留所有权利。
Prolactinomas are the most common functional pituitary adenomas. While dopamine agonists are a primary method of therapeutic treatment, the rate of resistance to these drugs continues to increase each year. During previous long-term clinical investigations, we found that partial resistant prolactinomas exhibited significantly more fibrosis than did sensitive adenomas, suggesting a role of fibrosis in their drug resistance. Furthermore, resistant adenomas with extensive fibrosis mainly express type I and type III collagens. Since TGF-beta 1 is the key factor in the initiation and development of tissue fibrosis, including in the pituitary, in this study, we aimed to determine whether TGF-beta 1 mediated fibrosis in prolactinomas and whether fibrosis was related to prolactinoma drug resistance. Using immunochemistry and western blotting, we found that the TGF-beta 1/Smad3 signaling pathway-related proteins were elevated in resistant prolactinoma specimens with high degrees of fibrosis compared to levels in sensitive samples, suggesting that this pathway may play a role in prolactinoma fibrosis. In vitro, TGF-beta 1 stimulation promoted collagen expression in normal HS27 fibroblasts. Furthermore, the sensitivity of rat prolactinoma MMQ cells to bro-mocriptine decreased when they were co-cultured with HS27 cells treated with TGF-beta 1. The TGF-beta 1 Smad3 signaling-specific inhibitor SB431542 counteracted these effects, indicating that TGF-beta 1/Smad3-mediated fibrosis was involved in the drug-resistant mechanisms of prolactinomas. These results indicate that SB431542 may serve as a promising novel treatment for preventing fibrosis and further improving the drug resistance of prolactinomas. (C) 2018 Elsevier B.V. All rights reserved.